Hepatocellular carcinoma (HCC) is one of the world's most common malignancies, causing almost one million deaths annually. HCC has a heterogeneous geographical distribution, which is probably related to differences in prevalence of risk factors among separate world areas. It is one of the most frequently occurring neoplasms in Asia, Africa and the Mediterranean basin.
The incidence of hepatocellular carcinoma is higher in areas with high carrier rates of hepatitis B and C and in patients with haemochromatosis. More than 80% of hepatocellular carcinomas occur in patients with cirrhotic livers. Once viral infection is established, about 10 years are required for patients to develop chronic hepatitis, 20 years to develop cirrhosis, and 30 years to develop carcinoma. In African and Asian countries, aflatoxin produced as a result of contamination of imperfectly stored staple crops by Apergillus flavus seems to be an independent risk factor for the development of hepatocellular carcinoma, probably through mutation of the p53 suppressor gene.
In patients with cirrhosis, the diagnosis of hepatocellular carcinoma should be suspected when there is deterioration in liver function, an acute complication (ascites, encephalopathy, variceal bleeding and jaundice) or development of upper abdominal pain and fever. Ultrasonography will identify most tumors, and the presence of a discrete mass within a cirrhotic liver together with an alpha-fetoprotein concentration above 500 ng/ml is diagnostic. Biopsy is unnecessary and should be avoided to reduce the risk of tumor seeding. Surgical resection is the only treatment that can offer a cure. However, because of the local spread of the tumor and the severity of pre-existing cirrhosis, such treatment is feasible in less than 20% of patients. Average operative mortality is 12% in cirrhotic patients, and five-year survival is around 15%.
Patients with cirrhosis and small tumors (5 cm or less) should have liver transplantation. Injection of alcohol or radio frequency ablation can improve survival in patients with small tumors who are unsuitable for transplantation. For larger tumors, trans-arterial embolization with lipiodol and cytotoxic drugs (cisplatin or doxorubicin) may induce tumor necrosis in some patients.
There are no absolute methods for diagnosing or assessing the degree of malignancy of tumors. However, among the methods available, microscopic examination of tissue is still the most reliable method for routine use. In a pathologic study, tumors can be graded by making an approximate assessment of the degree of structural dedifferentiation (anaplasia) based on histological and cytological criteria by microscopically examining sections of the tumors. However, on one hand, some cells may have lost their specific structural characters but still retain differentiated biochemical features, while others may still appear differentiated in structure but have lost many normal function attributes. On the other hand, a tumor is not homogeneous and may contain areas with more than one tumor grade. Therefore, a developed tumor may consist of a mixed population of cells that may differ in structure, function, growth potential, resistance to drugs or X-rays and ability to invade and metastasize. The two limitations reduce the effectiveness of histological examination of tumors. In another aspect, such an examination by sampling specimens is not suitable for investigations on a large scale.
Many attempts to find absolute markers of malignancy have been made. Other attempts to identify tumor-specific or tumor-associated proteins, either by direct measurement or by developing specific antibodies to these proteins, are still being made. They seem to be promising approaches not only in diagnosis but also in providing strategies to destroy cancer cells. A variety of substances wherein the presence or concentrations of the substances in vivo may be indicative for certain cancers have been reported, such as oncofetal antigens, e.g., alpha-fetoprotein; serum proteins, e.g., ferritin; enzymes; polyamines; ectopic hormones; cell markers; receptors or tumor-associated viral antigens. However, the most commonly used method of diagnosis of cancers depends on histology rather than any of the above substances. The lack of any absolute markers is a major deficiency in studying cancer.
Recent observations provide some contemplations in searching for the substances intimately associated with carcinogenesis. Cancer is appreciated as a result of multiple gene aberrations that cause both the activation of oncogenes and inactivation of tumor suppressor genes. Further, the differential expression of those critical genes associated with oncogenes can be reflected at the messenger RNA (mRNA) level in cells. For effectively screening the altered ones of interest amongst a great amount of mRNA, a powerful tool, specifically differential display, has been established to identify and isolate a small subset of genes which are differentially expressed between tumorous and normal cells (Liang et al., Cancer Research 52, 6966–6968, 1992).